Density of CD3+ and CD8+ Cells in the Microenvironment of Colorectal Cancer according to Prediagnostic Physical Activity

Abstract

IntroductionPhysical activity is associated not only with a decreased risk of developing colorectal cancer but also with improved survival. One putative mechanism is the infiltration of immune cells in the tumor microenvironment. Experimental findings suggest that physical activity may mobilize immune cells to the tumor. We hypothesized that higher levels of physical activity prior to colorectal cancer diagnosis are associated with higher densities of tumor-infiltrating T-lymphocytes in colorectal cancer patients. MethodThe study setting was a northern Swedish population-based cohort, including 109 792 participants with prospectively collected health-and lifestyle-related data. For 592 participants who later developed colorectal cancer, archival tumor tissue samples were used to assess the density of CD3+ and CD8+ cytotoxic T-cells by immunohistochemistry. Odds ratios for associations between selfreported, pre-diagnostic recreational physical activity and immune-cell infiltration were estimated by ordinal logistic regression. ResultsRecreational physical activity >3 times per week was associated with a higher density of CD8+ T-cells in the tumor front and center compared to participants reporting no recreational physical activity. Odds ratios were 2.77 (95% CI 1.21-6.35) and 2.85 (95% CI 1.28-6.33) for the tumor front and center, respectively, after adjustment for sex, age at diagnosis, and tumor stage. The risk estimates were consistent after additional adjustment for several potential confounders. For CD3 no clear associations were found. ConclusionPhysical activity may promote the infiltration of CD8+ immune cells in the tumor microenvironment of colorectal cancer. ImpactThe study provides some evidence on how physical activity may alter the prognosis in colorectal cancer on October 10, 2021.

Non-pharmaceutical interventions to optimize cancer immunotherapy

“…In this regard, the intriguing finding was presented that pre-diagnostic physical activity correlates with increased tumor CD8+ T cell infiltration in colorectal cancer, evident at both the tumor front and in the center. 42 These data suggest that physical activity may mobilize cytotoxic immune cells into evolving, yet-to-be-diagnosed tumors, thus having a ‘conditioning effect’ and possibly imposing a major marker for tumor immune surveillance and ICB response prediction. 43 In preclinical models of pancreatic ductal adenocarcinoma, aerobic exercise reduces tumor growth by fostering tumor immune surveillance on both the systemic and intratumoral level, with IL-15 Rα-expressing CD8+ T cells mediating the protective effect.…”

Opposing roles by KRAS and BRAF mutation on immune cell infiltration in colorectal cancer – possible implications for immunotherapy

“…For validation, retrospectively collected tumour specimens from CRC patients identified within a population-based cohort from northern Sweden, the Northern Sweden Health and Disease Study (NSHDS), were used. The NSHDS cohort has been described in detail previously [ 23 ]. Patients diagnosed between the years 2000–2016 with available tumour tissue for analyses of molecular traits and immune infiltration were included in this study ( n = 608).…”

“…The evaluation of cytotoxic T cells (CD8 + ) by immunohistochemistry in the NSHDS validation cohort has been previously described [ 23 ]. In brief, CD8 + cells were stained on whole tissue sections and semi-quantitatively evaluated at the tumour front of CRC specimens ( n = 608) ranging from score (1) no or sporadic, (2) moderate numbers, (3) abundant or (4) highly abundant.…”

Call for a holistic framework for cancer immunotherapy

“…Notably, an exercise‐dependent increase in tumor T‐cell infiltration was also observed in men, suggesting clinical relevance 12 . Exercise training may further have a “conditioning effect” because prediagnostic physical activity correlates with higher T‐cell infiltration in clinical cancer samples 14 . Importantly, physical activity also substantially improves quality of life and therapy tolerability in patients with cancer, thus having beneficial effects far beyond immune modulation 15–17 …”

“…12 Exercise training may further have a "conditioning effect" because prediagnostic physical activity correlates with higher T-cell infiltration in clinical cancer samples. 14 Importantly, physical activity also substantially improves quality of life and therapy tolerability in patients with cancer, thus having beneficial effects far beyond immune modulation. [15][16][17] Accumulating evidence suggests that psychological distress negatively affects cancer outcomes.…”